Combination of a 6-oxo-1,6-dihydro-pyridazine derivative having anti-cancer activity with an EGFR inhibitor

Abstract

A pharmaceutical composition of 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof in combination with N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.

The invention claimed is: 
     
       1. A method for treating non-small cell lung cancer, comprising administering to a subject in need thereof an effective synergistic amount of a pharmaceutical composition comprising 3-(1-{3[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof and N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide. 
     
     
       2. The method according to  claim 1 , comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl ]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate and N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide. 
     
     
       3. The method according to  claim 1 , wherein the 3 N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide is administered once or twice a day in an amount of 300 to 900 mg per administrationin. 
     
     
       4. The method according to  claim 1 , wherein the 3 N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide is administered once or twice a day in an amount of 300 to 900 mg per administration and the 3-(1-{3-[5-(1Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof and/or solvate thereof is administered in an amount of 250 mg to 12500 mg per week. 
     
     
       5. The method according to  claim 2 , wherein the 3 N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide is administered once or twice a day in an amount of 300 to 900 mg per administration and the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate is administered in an amount of 250 mg to 12500 mg per week. 
     
     
       6. The method according to  claim 1 , wherein the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof in combination with N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide is administered in a synergistic amount. 
     
     
       7. The method according to  claim 1 , wherein the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof is administered in an amount of 250 mg to 12500 mg per week. 
     
     
       8. The method according to  claim 2 , wherein the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate is administered in an amount of 250 mg to 12500 mg per week. 
     
     
       9. The method according to  claim 2 , wherein the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate in combination with N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide is administered in a synergistic amount. 
     
     
       10. The method according to  claim 1 , wherein the 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt thereof is administered in an amount of 250 mg to 12500 mg per week.